A mouse model of hepatic encephalopathy: bile duct ligation induces brain ammonia overload, glial cell activation and neuroinflammation.
Animals
Rats
Mice
Hepatic Encephalopathy
Ammonia
/ metabolism
Hyperammonemia
/ etiology
Kynurenine
Glutamine
/ metabolism
Tryptophan
Neuroinflammatory Diseases
Bile Ducts
/ surgery
Brain
/ metabolism
Disease Models, Animal
Microglia
/ metabolism
Liver Diseases
/ complications
Taurine
Choline
Bile Acids and Salts
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
20 10 2022
20 10 2022
Historique:
received:
03
07
2022
accepted:
14
10
2022
entrez:
20
10
2022
pubmed:
21
10
2022
medline:
25
10
2022
Statut:
epublish
Résumé
Hepatic encephalopathy (HE) is a common complication of chronic liver disease, characterized by an altered mental state and hyperammonemia. Insight into the brain pathophysiology of HE is limited due to a paucity of well-characterized HE models beyond the rat bile duct ligation (BDL) model. Here, we assess the presence of HE characteristics in the mouse BDL model. We show that BDL in C57Bl/6j mice induces motor dysfunction, progressive liver fibrosis, liver function failure and hyperammonemia, all hallmarks of HE. Swiss mice however fail to replicate the same phenotype, underscoring the importance of careful strain selection. Next, in-depth characterisation of metabolic disturbances in the cerebrospinal fluid of BDL mice shows glutamine accumulation and transient decreases in taurine and choline, indicative of brain ammonia overload. Moreover, mouse BDL induces glial cell dysfunction, namely microglial morphological changes with neuroinflammation and astrocyte reactivity with blood-brain barrier (BBB) disruption. Finally, we identify putative novel mechanisms involved in central HE pathophysiology, like bile acid accumulation and tryptophan-kynurenine pathway alterations. Our study provides the first comprehensive evaluation of a mouse model of HE in chronic liver disease. Additionally, this study further underscores the importance of neuroinflammation in the central effects of chronic liver disease.
Identifiants
pubmed: 36266427
doi: 10.1038/s41598-022-22423-6
pii: 10.1038/s41598-022-22423-6
pmc: PMC9585018
doi:
Substances chimiques
Ammonia
7664-41-7
Kynurenine
343-65-7
Glutamine
0RH81L854J
Tryptophan
8DUH1N11BX
Taurine
1EQV5MLY3D
Choline
N91BDP6H0X
Bile Acids and Salts
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
17558Informations de copyright
© 2022. The Author(s).
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